SMAD4 Loss in Colorectal Cancer Patients Correlates with Recurrence, Loss of Immune Infiltrate, and Chemoresistance

Isaac Wasserman; Lik Hang Lee; Shuji Ogino; Michael R Marco; Chao Wu; Xi Chen; Jashodeep Datta; Eran Sadot; Bryan Szeglin; Jose G Guillem; Philip B Paty; Martin R Weiser; Garrett M Nash; Leonard Saltz; Afsar Barlas; Katia Manova-Todorova; Srijaya Prakash Babu Uppada; Arthur E Elghouayel; Peter Ntiamoah; Jonathan N Glickman; Tsuyoshi Hamada; Keisuke Kosumi; Kentaro Inamura; Andrew T Chan; Reiko Nishihara; Andrea Cercek; Karuna Ganesh; Nancy E Kemeny; Punita Dhawan; Rona Yaeger; Charles L Sawyers; Julio Garcia-Aguilar; Marios Giannakis; Jinru Shia; J Joshua Smith

doi:10.1158/1078-0432.CCR-18-1726

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SMAD4 Loss in Colorectal Cancer Patients Correlates with Recurrence, Loss of Immune Infiltrate, and Chemoresistance

Journal article

Open access

Peer reviewed

SMAD4 Loss in Colorectal Cancer Patients Correlates with Recurrence, Loss of Immune Infiltrate, and Chemoresistance

Isaac Wasserman, Lik Hang Lee, Shuji Ogino, Michael R Marco, Chao Wu, Xi Chen, Jashodeep Datta, Eran Sadot, Bryan Szeglin, Jose G Guillem, …

Clinical cancer research, Vol.25(6), pp.1948-1956

2019-03-15

DOI: https://doi.org/10.1158/1078-0432.CCR-18-1726

PMCID: PMC6421131

PMID: 30587545

Abstract

Prognosis

Prospective Studies

Follow-Up Studies

Rectum - pathology

Biomarkers, Tumor - deficiency

Humans

Middle Aged

Male

Antineoplastic Combined Chemotherapy Protocols - pharmacology

Neoplasm Recurrence, Local - immunology

Neoplasm Recurrence, Local - pathology

Fluorouracil - therapeutic use

Colorectal Neoplasms - therapy

Adult

Female

Rectum - surgery

Colorectal Neoplasms - mortality

Smad4 Protein - immunology

Neoplasm Recurrence, Local - prevention & control

Colon - pathology

Drug Resistance, Neoplasm - immunology

Neoplasm Recurrence, Local - diagnosis

Colon - surgery

Xenograft Model Antitumor Assays

Disease-Free Survival

Animals

Colorectal Neoplasms - immunology

Antineoplastic Combined Chemotherapy Protocols - therapeutic use

Chemotherapy, Adjuvant - methods

Aged

Fluorouracil - pharmacology

Mice

Smad4 Protein - deficiency

Colorectal Neoplasms - pathology

Biomarkers, Tumor - immunology

Lymphocytes, Tumor-Infiltrating - immunology

SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death. A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance. The discovery cohort consisted of 364 patients with stage I-IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (interquartile range, 2.3-8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all < 0.04). SMAD4 loss was associated with worse RFS ( = 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS ( = 0.002 and = 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival. Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.132 Extracellular Matrix & Cell Differentiation; 1.132.306 TGF-Beta
Web Of Science research areas: Oncology
ESI research areas: Clinical Medicine

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Title: SMAD4 Loss in Colorectal Cancer Patients Correlates with Recurrence, Loss of Immune Infiltrate, and Chemoresistance
Creators: Isaac Wasserman - Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
Lik Hang Lee - Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
Shuji Ogino - Broad Institute of MIT and Harvard, Cambridge, Massachusetts
Michael R Marco - Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
Chao Wu - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
Xi Chen - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
Jashodeep Datta - Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
Eran Sadot - Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
Bryan Szeglin - Albert Einstein College of Medicine, New York, New York
Jose G Guillem - Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
Philip B Paty - Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
Martin R Weiser - Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
Garrett M Nash - Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
Leonard Saltz - Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
Afsar Barlas - Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York
Katia Manova-Todorova - Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York
Srijaya Prakash Babu Uppada - Department of Biochemistry and Molecular Biology, Buffet Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
Arthur E Elghouayel - College of William and Mary, Williamsburg, Virginia
Peter Ntiamoah - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
Jonathan N Glickman - Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Tsuyoshi Hamada - Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
Keisuke Kosumi - Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
Kentaro Inamura - Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
Andrew T Chan - Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
Reiko Nishihara - Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
Andrea Cercek - Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
Karuna Ganesh - Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
Nancy E Kemeny - Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
Punita Dhawan - Department of Biochemistry and Molecular Biology, Buffet Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
Rona Yaeger - Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
Charles L Sawyers - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
Julio Garcia-Aguilar - Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
Marios Giannakis - Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
Jinru Shia - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
J Joshua Smith - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
Publication Details: Clinical cancer research, Vol.25(6), pp.1948-1956
Publisher: United States
Grant note: U01 CA167552 / NCI NIH HHS R21 CA216746 / NCI NIH HHS UM1 CA167552 / NCI NIH HHS K07 CA190673 / NCI NIH HHS K24 DK098311 / NIDDK NIH HHS Howard Hughes Medical Institute I01 BX002086 / BLRD VA K07 CA122826 / NCI NIH HHS L30 CA209253 / NCI NIH HHS K08 CA230213 / NCI NIH HHS R01 CA124977 / NCI NIH HHS P01 CA087969 / NCI NIH HHS P30 CA008748 / NCI NIH HHS P30 CA036727 / NCI NIH HHS UM1 CA186107 / NCI NIH HHS R35 CA197735 / NCI NIH HHS R25 CA020449 / NCI NIH HHS P30 CA068485 / NCI NIH HHS R01 CA158472 / NCI NIH HHS P01 CA055075 / NCI NIH HHS R01 CA137178 / NCI NIH HHS R21 CA119005 / NCI NIH HHS R01 CA151993 / NCI NIH HHS R01 CA182551 / NCI NIH HHS
Academic Unit: UMMG Department of Surgery; Miller School of Medicine; UMMG Department of Public Health Sciences Research; UMMG Dept of Surgery - Div of Surgical Oncology
Language: English
Resource Type: Journal article
PMID: 30587545
PMCID: PMC6421131
Record Identifier: 991031575413202976